Spectrum of Clinical Manifestations in Children With WT1 Mutation: Case Series and Literature Review.

Background: Mutations of the Wilms tumor suppressor-1 gene (WT1) are associated with life-threatening glomerulopathy, disorders of sexual development, Wilm's tumor, and gonadal malignancies. Our objectives were to describe the clinical presentations, age of progression, and onset of complications of WT1 mutation through a case series and literature review. Methods: A retrospective study included all patients followed at the University of Miami/Holtz Children's Hospital from January 2000 to December 2020 with a diagnosis of WT1 mutation. A literature review of WT1 mutation cases was analyzed for clinical manifestations, karyotype, and long-term outcomes. Results: The WT1 mutation was identified in 9 children, median age at presentation of 0.9 years (range 1 week to 7 years). A total of four had female phenotypes, and 5 had abnormalities of male external genitalia, while all had XY karyotypes. All progressed to end-stage kidney disease (ESKD) and received a kidney transplant at a median age of 5 years (1.5-15 years). During a median time of follow-up of 9 years (range 2-28 years), there were 2 allograft losses after 7 and 10 years and no evidence of post-transplant malignancy. From 333 cases identified from the literature review, the majority had female phenotype 66% (219/333), but the predominant karyotype was XY (55%, 183/333). Of the female phenotypes, 32% (69/219) had XY sex reversal. Wilm's tumor occurred in 24%, predominantly in males with gonadal anomalies. Conclusions: Early recognition of WT1 mutation is essential for comprehensive surveillance of potential malignancy, avoidance of immunosuppressants for glomerulopathy, and establishing long-term multidisciplinary management.

Diabetic ketoacidosis drives COVID-19 related hospitalizations in children with type 1 diabetes.

BACKGROUND: Diabetes is a risk factor for poor COVID-19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies. METHODS: T1D Exchange coordinated a US type 1 diabetes COVID-19 registry. Forty-six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID-19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization. RESULTS: Data from 266 patients with previously established type 1 diabetes aged <19 years with COVID-19 were reported. Diabetic ketoacidosis (DKA) was the most common adverse outcome (n = 44, 72% of hospitalized patients). There were four hospitalizations for severe hypoglycemia, three hospitalizations requiring respiratory support (one of whom was intubated and mechanically ventilated), one case of multisystem inflammatory syndrome in children, and 10 patients who were hospitalized for reasons unrelated to COVID-19 or diabetes. Hospitalized patients (n = 61) were more likely than nonhospitalized patients (n = 205) to have minority race/ethnicity (67% vs 39%, P < 0.001), public insurance (64% vs 41%, P < 0.001), higher A1c (11% [97 mmol/mol] vs 8.2% [66 mmol/mol], P < 0.001), and lower insulin pump and lower continuous glucose monitoring use (26% vs 54%, P < 0.001; 39% vs 75%, P < 0.001). Age and gender were not associated with risk of hospitalization. Higher A1c was significantly associated with hospitalization, with an odds ratio of 1.56 (1.34-1.84) after adjusting for age, gender, insurance, and race/ethnicity. CONCLUSIONS: Higher A1c remained the only predictor for hospitalization with COVID-19. Diabetic ketoacidosis is the primary concern among this group.

Inequities in Diabetic Ketoacidosis Among Patients With Type 1 Diabetes and COVID-19: Data From 52 US Clinical Centers.

OBJECTIVE: We examined whether diabetic ketoacidosis (DKA), a serious complication of type 1 diabetes (T1D) was more prevalent among Non-Hispanic (NH) Black and Hispanic patients with T1D and laboratory-confirmed coronavirus disease 2019 (COVID-19) compared with NH Whites. METHOD: This is a cross-sectional study of patients with T1D and laboratory-confirmed COVID-19 from 52 clinical sites in the United States, data were collected from April to August 2020. We examined the distribution of patient factors and DKA events across NH White, NH Black, and Hispanic race/ethnicity groups. Multivariable logistic regression analysis was performed to examine the odds of DKA among NH Black and Hispanic patients with T1D as compared with NH White patients, adjusting for potential confounders, such as age, sex, insurance, and last glycated hemoglobin A1c (HbA1c) level. RESULTS: We included 180 patients with T1D and laboratory-confirmed COVID-19 in the analysis. Forty-four percent (n = 79) were NH White, 31% (n = 55) NH Black, 26% (n = 46) Hispanic. NH Blacks and Hispanics had higher median HbA1c than Whites (%-points [IQR]: 11.7 [4.7], P < 0.001, and 9.7 [3.1] vs 8.3 [2.4], P = 0.01, respectively). We found that more NH Black and Hispanic presented with DKA compared to Whites (55% and 33% vs 13%, P < 0.001 and P = 0.008, respectively). After adjusting for potential confounders, NH Black patients continued to have greater odds of presenting with DKA compared with NH Whites (OR [95% CI]: 3.7 [1.4, 10.6]). CONCLUSION: We found that among T1D patients with COVID-19 infection, NH Black patients were more likely to present in DKA compared with NH White patients. Our findings demonstrate additional risk among NH Black patients with T1D and COVID-19.

EARLY ONSET OF MODY5 DUE TO HAPLOINSUFFICIENCY OF HNF1B.

OBJECTIVE: To report 2 patients with haploinsufficiency of hepatic nuclear factor 1 homeobox B (HNF1B) that results in the onset of maturity onset diabetes of the young type 5 (MODY5) before 3 years of age. METHODS: We present 2 unusual patients with MODY5 that was diagnosed at 33 and 22 months of age, respectively. We describe the presentations, clinical course, and genetic tests of both patients, and lastly, we review the literature on the prevalence and the age of presentation of MODY5 both in children and in adult patients. RESULTS: The first patient had severe congenital renal dysplasia, and deoxyribonucleic acid microarray indicated the deletion of 17q12. Hemoglobin A1c (HbA1c) was obtained due to the concern of MODY5, and the initial level (6.6%, 49 mmol/mol) was abnormally elevated. The second patient had mild renal dysplasia and 17q12 deletion encompassing the HNF1B gene. Hyperglycemia was identified during an episode of respiratory illness. HbA1c (6.2%, 44 mmol/mol) level was abnormally elevated. Pancreatic autoantibodies were absent in both patients. Diet modification resulted in an improvement of HbA1c in both patients. CONCLUSION: Our report highlights the importance of considering MODY5 in patients with congenital anomalies of kidney. Identification of children with MODY5 permits early management of hyperglycemia.

A neonate with mucolipidosis II and transient secondary hyperparathyroidism.

Background Mucolipidosis II α/ß (ML II) is an autosomal recessive disease associated with the abnormality of lysosomal enzyme trafficking. Case presentation We present an unusual patient with: (a) marked skeletal anomalies with secondary hyperparathyroidism; (b) serum intact parathyroid hormone level normalized by 7 weeks but abnormally elevated serum alkaline phosphate persisted; and (c) two mutations identified in the GNPTAB gene. One mutation, c.3503_3504delTC, is the most common mutation in ML II. However, the second mutation, c.2896delA, is a rare mutation for which clinical presentation has not been described previously.

Vitamin D status among preterm infants with cholestasis and metabolic bone disease.

BACKGROUND: Metabolic bone disease of prematurity (MBD) is a common problem among preterm infants. Our previous study identified cholestasis as an important risk factor for the development of MBD. We conducted this study to determine the vitamin D status in preterm infants with MBD and cholestasis. METHODS: We retrospectively reviewed medical record of preterm infants evaluated in NICU at Holtz Children's/Jackson Memorial Hospital between June 2014 and May 2016. Demographic, biochemical data, and vitamin D intake were collected and analyzed. RESULTS: We identified 58 preterm infants (median gestational age 25 weeks) with MBD during this period. Twenty five infants also developed cholestasis. Median serum 25-hydroxyvitamin D level at the time of diagnosis of MBD was similar in cholestasis (C), (29.1 ng/ml, IQR 24.4-33.5), and non-cholestasis (NC), (28.7 ng/ml, IQR 22.7-34.6), group (p = 0.41). At the second measurement, average 6 weeks after the first measurement; median serum 25-hydroxyvitamin D level was lower (p = 0.02) in the C group (31.2 ng/ml, IQR 23.0-38.8) than in the NC group (36.5 ng/ml, IQR 28-45). However, the actual percentage of infants with vitamin D deficiency was similar in both the groups. CONCLUSION: Most preterm infants with cholestasis and MBD had normal vitamin D status.

Associations of Insulin Resistance and Glycemia With Liver Enzymes in Hispanic/Latino Youths: Results From the Hispanic Community Children's Health Study/Study of Latino Youth (SOL Youth).

BACKGROUND: Associations of insulin resistance and hyperglycemia with a panel of liver enzymes have not been well studied in a young, heterogenous Hispanic/Latino population. We aimed to assess the associations of insulin resistance and glycemia with nonalcoholic fatty liver disease (NAFLD), as measured by liver enzymes and the pediatric NAFLD fibrosis index (PNFI), and whether these associations are modified by body mass index and mediated by inflammation or endothelial dysfunction. MATERIALS AND METHODS: We conducted a cross-sectional study of 1317 boys and girls aged 8 to 16 years from the Hispanic Community Children's Health Study/Study of Latino Youth. We used Poisson regression to assess the associations of fasting glucose, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) with elevated alanine aminotransferase (ALT) (>25 U/L in boys, >22 U/L in girls), aspartate aminotransferase (AST) (≥37 U/L), gamma-glutamyl transpeptidase (GGT) (≥17 U/L), and PNFI (≥9; a function of age, waist circumference, and triglyceride level). RESULTS: HOMA-IR was associated with elevated ALT, AST, GGT, and PNFI [prevalence ratios (95% confidence intervals) for each 1-unit increase in the natural log of HOMA-IR: 1.99 (1.40-2.81), 2.15 (1.12-4.12), 1.70 (1.26-2.30), and 1.98 (1.43-2.74), respectively]. Associations were observed in overweight/obese children, but not in normal weight children (P-interaction=0.04 for AST and P-interaction=0.07 for GGT). After further adjustment for adiponectin, high-sensitivity C-reactive protein, e-selectin, and PAI-1, associations of HOMA-IR with liver enzymes and PNFI were attenuated, but remained statistically significant for AST and PNFI. CONCLUSION: Insulin resistance was associated with NAFLD in overweight/obese Hispanic/Latino youth, and this association may be partially mediated by inflammation and endothelial dysfunction.

Duplication of SOX9 is not a common cause of 46,XX testicular or 46,XX ovotesticular DSD.

BACKGROUND: Translocation of the SRY gene to the paternal X chromosome is the explanation for testis development in the majority of subjects with 46,XX testicular disorder of sexual development (DSD). However, nearly all subjects with 46,XX ovotesticular DSD and up to one third of subjects with 46,XX testicular DSD lack SRY. SRY-independent expression of SOX9 has been implicated in the etiology of testis development in some individuals. METHODS: We amplified microsatellite markers in the region of SOX9 from a cohort of 30 subjects with either 46,XX testicular or 46,XX ovotesticular DSD to detect SOX9 duplications. RESULTS: Duplication of the SOX9 region in 17q was not detected in any subject. CONCLUSION: Duplication in the region of 17q that contains SOX9 is not a common cause of testis development in subjects with SRY-negative 46,XX testicular or ovotesticular DSD.

A nine year old girl with thyrotoxicosis, ataxia, and chorea.

Neurologic manifestations are common in patients with thyroid disease. We describe the case of a nine year old girl with Graves disease and the unique combination of chorea and ataxia that both resolved after treatment of hyperthyroidism.

46,XX sex reversal with partial duplication of chromosome arm 22q.

We present a case of 46,XX sex reversal in the absence of SRY but with partial duplication of chromosome 22q. The subject had multiple congenital anomalies but nearly complete masculinization of the external genitalia. Our case along with a previous case supports the existence of a gene on chromosome 22q that can trigger testis determination in the absence of SRY. We proposed that overexpression of the SOX10 gene at 22q13 might be the cause of sex reversal. We investigated 13 additional subjects with SRY-negative 46,XX sex reversal for microduplication of chromosome arm 22q in the region of SOX10 gene, but could not find evidence for it.